Use of novel nano-formulation containing gingerenone a in preparation of Anti-tumor drug

Abstract

Disclosed in the present invention is a use of a novel nano-formulation containing gingerenone A in the preparation of an anti-tumor drug. The nano-formulation comprises aminated dendritic mesoporous silica and gingerenone A loaded on the aminated dendritic mesoporous silica.

Description

Application of a novel nano-formulation containing gingerone A in the preparation of antitumor drugs Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to the application of a novel nano-formulation containing gingerone A in the preparation of antitumor drugs. Background Technology

[0002] Currently, the incidence and mortality rates of malignant tumors in my country continue to rise, with annual medical expenses exceeding 220 billion yuan. Existing treatments for tumors mainly involve surgical resection, chemotherapy, and radiotherapy, but all have limitations such as strong side effects and a high recurrence rate. Therefore, screening for novel, safe, and effective anti-tumor drugs is of great clinical significance.

[0003] Gingerenone A (GA) is a natural phytochemical extracted from ginger with broad medicinal value, including anti-tumor, antioxidant, anti-aging, anti-inflammatory, antiviral, and blood sugar control effects. Studies have shown that GA can promote anti-proliferation and senescence of breast cancer cells induced by oxidative stress (Gingerenone A Induces Antiproliferation and Senescence of Breast Cancer Cells. Antioxidants.; Tzu-Jung Yu.; et al.). Simultaneously, GA selectively kills cancer cells through dual inhibition of JAK2 and S6K1 (Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase 1 (S6K1) Pathways.; Sanguine Byun.; et al.), making it an effective anti-tumor active ingredient.

[0004] However, due to the poor solubility, permeability, stability and absorption of gingerone A, it is difficult to achieve an effective therapeutic concentration and thus the expected effect, which greatly limits its application scope.

[0005] Summary of the Invention

[0006] The purpose of this invention is to overcome the aforementioned deficiencies in the existing technology and provide a novel nano-formulation containing gingerone A for the preparation of antitumor drugs. This nano-formulation utilizes aminated dendritic mesoporous silica to load gingerone A, resulting in a novel nano-formulation with high drug loading capacity, high encapsulation efficiency, and high biocompatibility. This formulation exhibits low cytotoxicity, can be rapidly taken up by tumor cells, significantly enhances the ability of gingerone A to clear tumor cells, and effectively inhibits tumor proliferation in vivo. Its therapeutic effect is superior to that of the commonly used clinical antitumor drug dabrafenib, and it has broad application prospects.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] The application of a novel nanoformulation containing gingerone A in the preparation of antitumor drugs, wherein the nanoformulation comprises aminated dendritic mesoporous silica and gingerone A loaded on the aminated dendritic mesoporous silica.

[0009] Optionally, the tumor includes one or more of the following: melanoma, lymphohematopoietic system tumors, endocrine tumors, lung and mediastinal tumors, breast tumors, digestive system tumors, urinary and male reproductive system tumors, female reproductive system tumors, head and neck tumors, central nervous system tumors, skin tumors, and bone and soft tissue tumors.

[0010] Optionally, the dosage form of the drug includes tablets, capsules, pills, injections, sustained-release formulations, or controlled-release formulations.

[0011] Optionally, the route of administration of the antitumor drug includes one or more of the following: intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, rectal administration, skin and mucous membrane administration, and inhalation administration.

[0012] Optionally, the dosage of the nano-formulation in the antitumor drug is 100 mg / kg to 400 mg / kg.

[0013] Optionally, the antitumor drug is a drug that inhibits tumor growth or tumor cell proliferation.

[0014] Optionally, the antitumor drug is a drug that promotes or induces apoptosis in tumor cells.

[0015] Optionally, the antitumor drug is a drug that inhibits the growth of transplanted tumors.

[0016] Optionally, the antitumor drug may also contain pharmaceutically acceptable carriers, excipients, and / or excipients.

[0017] Optionally, the loading of gingerone A in the nano-formulation is 15% to 30%.

[0018] Optionally, the encapsulation rate of gingerone A in the nano-formulation is 11% to 35%.

[0019] Optionally, the particle size of the nano-formulation is 50 nm to 200 nm.

[0020] Optionally, the specific surface area of ​​the nano-formulation is 800 m². 2 / g~1000m 2 / g.

[0021] Optionally, the particle size of the aminated dendritic mesoporous silica is 50 nm to 200 nm.

[0022] Optionally, the pore size of the aminated dendritic mesoporous silica is 2 nm to 10 nm.

[0023] Optionally, the specific surface area of ​​the aminated dendritic mesoporous silica is 300 m². 2 / g~1000m 2 / g.

[0024] Optionally, the preparation method of the nano-formulation includes:

[0025] Shogaol A is dissolved in a solvent to obtain a shogaol A solution. The shogaol A solution and aminated dendritic mesoporous silica are added to a buffer solution to react and load the shogaol A onto the aminated dendritic mesoporous silica to obtain the nano-formulation.

[0026] The mass ratio of gingerone A to aminated dendritic mesoporous silica in the gingerone A solution is (1-5):1.

[0027] The buffer solution includes one or more of the following: phosphate buffer, borate buffer, citrate buffer, phosphate and trimethylolpropane, acetate buffer, imidazole buffer, and carbonate buffer.

[0028] The pH of the buffer solution is 5.0 to 7.4.

[0029] The concentration of gingerone A in the gingerone A solution is 2 mg / mL to 6 mg / mL.

[0030] The solvent includes any one of acetone, acetonitrile, ethanol, methanol, and dimethyl sulfoxide.

[0031] The reaction temperature is 25℃~80℃; the reaction time is 6h~36h.

[0032] This invention also discloses an anti-tumor drug, the active ingredient of which is a novel nano-formulation containing gingerone A; the nano-formulation is the nano-formulation used in the above-mentioned application.

[0033] Implementing the embodiments of the present invention will have the following beneficial effects:

[0034] (1) This invention uses aminated dendritic mesoporous silica to load gingerone A to prepare a novel nano-formulation containing gingerone A with high drug loading, high encapsulation rate and high biocompatibility. This formulation has low cytotoxicity, can be rapidly taken up by tumor cells, significantly enhances the ability of gingerone A to clear tumor cells, effectively inhibits the proliferation of tumors in vivo, and its therapeutic effect is superior to that of commonly used anti-tumor drugs such as dabrafenib. It can be applied to anti-cancer drugs and has broad application prospects.

[0035] (2) In this invention, amino-modified dendritic mesoporous silica is selected as a drug carrier, and gingerone A is loaded onto it through non-covalent forces, so that the nano-formulation is highly enriched at the tumor site, thereby achieving the effect of targeting the tumor and improving the bioavailability of gingerone A.

[0036] (3) The experimental results of this invention show that the nano-formulation containing gingerone A can significantly inhibit the proliferation of A431 human epidermal cancer cells, A375 human malignant melanoma cells, Caco2 human colon adenocarcinoma cells, SW579 human thyroid squamous cell carcinoma cells, HCT-116 human colorectal cancer cells, and HepG2 human liver cancer cells, and has a wide range of anti-tumor effects, especially significant effects against melanoma; and it shows a good inhibitory effect on tumor growth in mouse xenograft models, and has no obvious toxic side effects. It has good application prospects and high application value in the preparation of anticancer drugs, and the preparation method of the drug formulation is simple, low in cost, and the finished drug has good economic benefits. Attached Figure Description

[0037] Figure 1 shows the effect of different concentrations of GA@AMSN and GA on the proliferation of A431 human epidermal cancer cells in Example 2 of the present invention.

[0038] Figure 2 shows the effect of different concentrations of GA@AMSN and GA on the proliferation of A375 human malignant melanoma cells in Example 2 of the present invention.

[0039] Figure 3 shows the effect of different concentrations of GA@AMSN and GA on the proliferation of Caco2 human colon adenocarcinoma cells in Example 2 of the present invention.

[0040] Figure 4 shows the effect of different concentrations of GA@AMSN and GA on the proliferation of SW579 human thyroid squamous cell carcinoma cells in Example 2 of the present invention.

[0041] Figure 5 shows the effect of different concentrations of GA@AMSN and GA on the proliferation of HCT-116 human colorectal cancer cells in Example 2 of the present invention.

[0042] Figure 6 shows the effect of different concentrations of GA@AMSN and GA on the proliferation of HepG2 human liver cancer cells in Example 2 of the present invention.

[0043] Figure 7 shows the pharmacodynamic evaluation of the test drug in the A375 cell mouse subcutaneous xenograft model of Example 2 of the present invention (A, tumor growth curve; B, tumor weight; C, tumor image).

[0044] Figure 8 shows the pharmacodynamic evaluation of the test drug in the A375 cell mouse subcutaneous xenograft model of Example 2 of the present invention (A, curve of weight change of tumor-bearing mice; B, curve of relative weight change of tumor-bearing mice).

[0045] Figure 9 shows the liver H&E staining results after treatment with the test drug (GA@AMSN) for 2 days in Example 2 of this invention. Detailed Implementation

[0046] The present invention will be further described below with reference to specific embodiments, but this does not limit the present invention in any way.

[0047] This invention discloses the application of a novel nano-formulation containing gingerone A in the preparation of antitumor drugs. The nano-formulation includes aminated dendritic mesoporous silica and gingerone A loaded on aminated dendritic mesoporous silica.

[0048] In one specific embodiment, the tumor includes one or more of the following: melanoma, lymphohematopoietic system tumor, endocrine tumor, lung and mediastinal tumor, breast tumor, digestive system tumor, urinary and male reproductive system tumor, female reproductive system tumor, head and neck tumor, central nervous system tumor, skin tumor, and bone and soft tissue tumor.

[0049] In one specific embodiment, the dosage form of the drug includes tablets, capsules, pills, injections, sustained-release formulations, or controlled-release formulations.

[0050] In one specific embodiment, the route of administration of the antitumor drug includes one or more of the following: intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, rectal administration, skin and mucous membrane administration, and inhalation administration.

[0051] In one specific embodiment, the dosage of the nano-formulation in the anticancer drug is 100 mg / kg to 400 mg / kg.

[0052] In one specific embodiment, the antitumor drug is a drug that inhibits tumor growth or inhibits tumor cell proliferation.

[0053] In one specific embodiment, the antitumor drug is a drug that promotes or induces apoptosis in tumor cells.

[0054] In one specific embodiment, the antitumor drug is a drug that inhibits the growth of transplanted tumors.

[0055] In one specific embodiment, the antitumor drug further comprises a pharmaceutically acceptable carrier, excipients, and / or excipients.

[0056] In one specific embodiment, the loading of gingerone A in the nano-formulation is 15% to 30%.

[0057] In one specific embodiment, the encapsulation rate of gingerone A in the nanoformulation is 11% to 35%.

[0058] In one specific embodiment, the particle size of the nano-formulation is 50 nm to 200 nm.

[0059] In one specific embodiment, the specific surface area of ​​the nanoformulation is 800 m² / g to 1000 m² / g.

[0060] In one specific embodiment, the particle size of the aminated dendritic mesoporous silica is 50 nm to 200 nm.

[0061] In one specific embodiment, the pore size of the aminated dendritic mesoporous silica is 2 nm to 10 nm.

[0062] In one specific embodiment, the specific surface area of ​​the aminated dendritic mesoporous silica is 300 m². 2 / g~1000m 2 / g.

[0063] In one specific embodiment, the method for preparing nano-formulations includes:

[0064] (1) The template agent and catalyst are added to water and mixed to form an aqueous phase.

[0065] (2) Mix the silicon source with the solvent to form an oil phase.

[0066] (3) The oil phase and the aqueous phase are subjected to a homogeneous reaction. After the reaction is completed, the mixture is centrifuged, dried and calcined to obtain dendritic mesoporous silica.

[0067] (4) Add dendritic mesoporous silica and an ammonia source to an acetonitrile solution for amination modification to obtain amination-modified dendritic mesoporous silica.

[0068] (5) Dissolve gingerone A in a solvent to obtain gingerone A solution. Add gingerone A solution and aminated dendritic mesoporous silica to a buffer solution to react and load gingerone A onto aminated dendritic mesoporous silica to obtain nano-formulation.

[0069] Specifically, this invention first prepares dendritic mesoporous silica with a unique central radial pore structure in a water / oil two-phase system. Then, it modifies the surface with amino groups. Compared with traditional mesoporous silica, this invention selects dendritic mesoporous silica with higher pore permeability, larger pore volume, multiple surface functions and good biocompatibility as a drug carrier. It further modifies the surface with amino groups, and uses aminated dendritic mesoporous silica as a carrier to achieve high loading of gingerone A through non-covalent forces. The resulting nano-formulation has uniform particle size and features high drug loading, high encapsulation efficiency, high biocompatibility and low toxicity.

[0070] Furthermore, the present invention optimizes the preparation conditions to control the structure of mesoporous silica nanomaterials, including particle size, pore size, specific surface area, etc., which is beneficial to forming a mesoporous structure with a better pore size distribution.

[0071] In one specific embodiment, the mass ratio of gingerone A to aminated dendritic mesoporous silica in the gingerone A solution is (1-5):1.

[0072] In one specific embodiment, the buffer solution includes one or more of the following: phosphate buffer, borate buffer, citrate buffer, phosphate and trimethylolmethane, acetate buffer, imidazole buffer, and carbonate buffer.

[0073] In one specific embodiment, the pH of the buffer solution is 5.0 to 7.4.

[0074] In one specific embodiment, the concentration of gingerone A in the gingerone A solution is 2 mg / mL to 6 mg / mL.

[0075] In one specific embodiment, the solvent in step (5) includes any one of acetone, acetonitrile, ethanol, methanol, and dimethyl sulfoxide.

[0076] In one specific embodiment, the homogeneous reaction temperature is 25°C to 80°C; the homogeneous reaction time is 6h to 36h.

[0077] In one specific embodiment, the template agent includes one or two of hexadecyltrimethylammonium chloride, octadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, hexadecylpyridinium chloride, and dodecyltrimethylammonium bromide. Preferably, the template agent is hexadecyltrimethylammonium chloride.

[0078] In one specific embodiment, the catalyst includes one or more of triethanolamine, tripropanolamine, diethanolamine, ethanolamine, and ammonia. Preferably, the catalyst is triethanolamine.

[0079] In one specific embodiment, the silicon source includes one or more of tetraethyl orthosilicate, methyl orthosilicate, tetra(2-methoxy-1-methylethyl)silicate, tetraisopropyl orthosilicate, tetrabutyl orthosilicate, and tetraisopropyl orthosilicate. Preferably, the silicon source is tetraethyl orthosilicate.

[0080] In one specific embodiment, the ammonia source includes one or more of 3-aminopropyltriethoxysilane, 3-aminopropyltrimethoxysilane, N-(2-aminoethyl)-3-aminopropyltriethoxysilane, and γ-aminopropyldiethoxymethylsilane. Preferably, the ammonia source is 3-aminopropyltriethoxysilane.

[0081] In one specific embodiment, the solvent in step (2) includes one or more of chlorobenzene, cyclohexane, chloroform, dichloromethane, and water.

[0082] In one specific embodiment, the preparation method of aminated dendritic mesoporous silica specifically includes: adding a template agent and a catalyst to water and mixing them at 40℃~60℃ for 10min~30min to form an aqueous phase, and adding a chlorobenzene solution containing a silicon source, wherein the mass ratio of the template agent, catalyst and silicon source is (20~30):(0.5~1.2):(6~12), mixing at 40℃~60℃ for 12h~36h, centrifuging and drying, and calcining at 300℃~600℃ for 4h~8h to obtain dendritic mesoporous silica; adding the dendritic mesoporous silica and an ammonia source at a mass ratio of (0.08~0.1):(50~100) to an acetonitrile solution, and reacting at 60℃~85℃ for 8h~16h to achieve amination modification to obtain aminated dendritic mesoporous silica.

[0083] In one specific embodiment, the present invention does not have a special limitation on the mixing method, as long as the raw materials are mixed evenly.

[0084] This invention also discloses an anti-tumor drug, the active ingredient of which is a novel nano-formulation containing gingerone A.

[0085] The following are specific embodiments.

[0086] Example 1: Preparation of a novel nano-formulation containing gingerone A (GA@AMSN)

[0087] Preparation of MSN: 30 g of N-hexadecyltrimethylammonium chloride (CTAC) was dissolved in 300 mL of ultrapure water in a 500 mL round-bottom flask. Then, 1.0 g of triethanolamine was added to the dissolved CTAC solution and stirred thoroughly to form an upper aqueous phase. Next, 12 mL of tetraethyl silicate was thoroughly mixed with 100 mL of solvent (60 mL cyclohexane + 40 mL chlorobenzene) in a beaker, and this was used as the oil phase. The oil phase was transferred to a flask to form a two-phase reaction system. The reaction was carried out at 60 °C with stirring at 300 rpm / min for 12 h. The resulting milky white liquid was removed and centrifuged (10000 rpm, 15 min) to obtain a white solid product. The product was washed three times with ethanol to remove the solvent, and then dried in air to obtain a white powder. The white powder was placed in a muffle furnace and calcined at 550℃ for 6 hours to remove CTAC. The resulting product was washed once with deionized water and once with ethanol, and then vacuum dried to obtain MSN, which had a specific surface area of ​​926.3128 m². 2 / g, pore size 8.5612nm, pore volume 3.374020cm³ 3 / g.

[0088] Preparation of AMSN: 200 mg MSN was added to 40 mL of acetonitrile and ultrasonically dispersed. 200 μl of 3-aminopropyltriethoxysilane (APTE) was added to the reaction system, and the mixture was stirred at 80 °C and 600 rpm for 12 h. After the reaction was completed, the liquid was centrifuged, and the resulting sample was washed twice with water and twice with ethanol to obtain AMSN.

[0089] Preparation of GA@AMSN: 40 mg AMSN was added to 5 mL of GA in acetonitrile solution (5 mg / mL, 10 mg / mL, 15 mg / mL). The mixture was ultrasonically dispersed and incubated at room temperature for 8 h with stirring. Then, the mixture was centrifuged, the supernatant was removed, the product was collected, washed three times with deionized water, and dried under vacuum to obtain GA@AMSN.

[0090] Example 2: GA@AMSN In Vitro Tumor Cell Viability Assay

[0091] 1. Experimental cells

[0092] A431 human epidermal cancer cells, A375 human malignant melanoma cells, Caco2 human colon adenocarcinoma cells, SW579 human thyroid squamous cell carcinoma cells, HCT-116 human colorectal cancer cells, and HepG2 human liver cancer cells were purchased from the Cell Bank of the Chinese Academy of Sciences Type Culture Collection Committee.

[0093] 2. Experimental Methods

[0094] The effect of GA@AMSN prepared in Example 1 on cell proliferation was analyzed using the MTT assay. Tumor cell proliferation was investigated by dividing the GA@AMSN in 96-well plates by 1×10⁻⁶ cells / well. 4 Cells were seeded per well. After cell adhesion, 100 μL of culture medium containing the corresponding drug concentrations (5 μM–25 μM) of GA@AMSN and GA were added to each well. Six replicates were set for each concentration, with an error margin of no more than 5% per well. After 24 hours of drug treatment, the supernatant was discarded, and 100 μL of 5 mg / ml MTT solution was added to each well. Incubation continued for 3 hours, then the culture was terminated, and the supernatant was carefully discarded. 100 μL of DMSO was added to each well to dissolve any crystals. The absorbance of each well was measured at 490 nm using an ELISA reader, and the IC50 value was calculated.

[0095] As shown in Figures 1-6, the GA@AMSN of the present invention has a good synergistic inhibitory effect. After 24 hours of treatment, it can dose-dependently inhibit the proliferation of A431 human epidermal cancer cells, A375 human malignant melanoma cells, Caco2 human colon adenocarcinoma cells, SW579 human thyroid squamous cell carcinoma cells, HCT-116 human colorectal cancer cells, and HepG2 human liver cancer cells.

[0096] Example 3: Experimental results of the GA@AMSN mouse tumor model

[0097] Based on the experimental results of Example 2, this example compares the effects of GA@AMSN and positive control drugs on A375 melanoma as follows:

[0098] 1. Laboratory animals:

[0099] Female NU / NU mice, 6-8 weeks old and weighing 18-22g, were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. All mice were housed in the Shanghai Lidi SPF-grade animal facility and acclimatized to the environment for at least 3 days beforehand. All mice were housed in the SPF-grade IVC (Indoor Temperature and Pressure) system, with a temperature of 20-26℃, humidity of 40-70%, and a 12-hour light-dark cycle. No more than 6 mice were housed in each cage, which measured 325mm × 210mm × 180mm. The bedding in the cages was autoclaved corn cobs, which were changed twice weekly. Throughout the experiment, all mice had free access to food and drink. Feed was sterilized by Co60 irradiation, and drinking water was autoclaved. Sufficient supply of both food and water was maintained.

[0100] 2. Experimental Design

[0101] 2.1 Culture of A375 tumor cells

[0102] A375 cells were cultured in 90% DMEM + 10% inactivated FBS at 37°C in a 5% CO2 incubator. Cells in the logarithmic growth phase will be used to establish an in vivo xenograft model.

[0103] 2.2, A375 tumor cell inoculation

[0104] A375 cells in logarithmic growth phase were resuspended in an appropriate amount of HBSS, counted, and the cell density was adjusted to 4 × 10⁻⁶ cells / year. 7 The cells / mL were stored on ice for later use. 0.1 mL of tumor cell suspension (4 × 10⁶ cells / mL) was subcutaneously injected into the right side of each NU / NU mouse. 6 Cells / each. Tumors with an average volume of 109.65 (84.69–136.81) mm were selected. 3 Fifteen mice were randomly divided into three groups of five each for pharmacodynamic analysis. The three groups were administered PBS, gingerone A nanoparticles (GA@AMSN), and the positive control drug dabrafenib, respectively. Detailed administration methods, dosages, and routes of administration are shown in Table 1. Day 0 was the day of administration for each group.

[0105] Table 1. Grouping and Dosage

[0106] Dosage volume: Adjust the dosage volume according to the body weight of tumor-bearing mice (10 μL / g).

[0107] 3. Evaluation Indicators

[0108] The main objective was to establish subcutaneous xenografts in the A375 cell line and evaluate the antitumor activity of the test drug in this model.

[0109] 3.1 Tumor volume: Measured twice weekly using vernier calipers. The tumor volume was calculated using the formula V = 0.5 × (a × b) 2 ), where a and b represent the long and short diameters of the tumor, respectively.

[0110] 3.2 Tumor growth inhibition rate TGI (%) = [1 - (Ti - T0) / (Vi - V0)] × 100

[0111] Where Ti is the average tumor volume after the start of administration in the compound group, T0 is the average tumor volume at the first administration in the compound group, V0 is the average tumor volume at the first administration in the solvent control group, and Vi is the average tumor volume after the start of administration in the solvent control group.

[0112] 3.3 Relative Tumor Proliferation Rate (T / C%): The calculation formula is as follows: T / C% = TRTV / CRTV × 100% (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). The relative tumor volume (RTV) is calculated based on the tumor measurement results. The calculation formula is RTV = Vt / V0, where V0 is the average tumor volume measured when the group is administered the drug (i.e., d0), and Vt is the average tumor volume at a certain measurement. TRTV and CRTV are based on data from the same day.

[0113] 3.4 The body weight of all tumor-bearing mice was measured twice a week. The percentage change in body weight after administration was calculated: RCBW(%) = (BWi - BW0) / BW0 × 100, where BWi is the average body weight after the start of administration and BW0 is the average body weight at the time of the first administration.

[0114] 4. Data Analysis

[0115] All data were analyzed using Graphpad and expressed as mean ± SEM. Differences between the test drug group and the control group were compared using the One-way ANOVA LSD(L) test; p < 0.05 was considered statistically significant.

[0116] 5. Results

[0117] On day 21 of drug administration, the mean tumor volume in the model control group (PBS) was 2075.28 ± 384.4 mm. 3 The mean tumor volume in the GA@AMSN, 100 mg / kg group and the Dabrafenib, 100 mg / kg group was 1184.15 ± 212.76 mm. 3 1211.51±130.65mm 3 Compared with the model control group, the tumor growth inhibition rate (TGI%) was 45.34% and 43.95%, respectively. All treatment groups inhibited the growth of subcutaneous xenografts in A375 mice, although the difference was not statistically significant (p > 0.05). On day 25 of administration, the mean tumor volume in the GA@AMSN, 100 mg / kg group and the Dabrafenib, 100 mg / kg group was 1900.7 ± 384.05 mm. 3 1985.26±230.72mm 3 See Table 2 and Figure 7.

[0118] On day 21 of group drug administration, the average tumor volume of mice in the model control group exceeded 2000 mm. 3Due to the requirements of a humane endpoint, euthanasia was performed on the same day. The experiment ended on day 25. All mice in the GA@AMSN, 100 mg / kg and Dabrafenib, 100 mg / kg groups were euthanized, their tumors were removed, weighed, and photographed. The average tumor weight in the model control group was 2.11 ± 0.36 g (day 21); the average tumor weights in the GA@AMSN, 100 mg / kg and Dabrafenib, 100 mg / kg groups were 2.02 ± 0.41 g (day 25) and 2.07 ± 0.27 g (day 25), respectively. The tumor volume and tumor weight results were largely consistent, as shown in Table 3 and Figure 7.

[0119] In addition, no mice showed a continuous decrease in weight or other abnormal symptoms in this experiment, indicating that the tumor-bearing mice were able to tolerate the drug at the administered dose, as shown in Table 4 and Figure 8.

[0120] Table 2. Mean tumor volume (Mean ± SEM) in each group of mice Note: *p<0.05 is considered statistically significant compared to the control group.

[0121] Table 3. Mean tumor weight in mice of each group (Mean±SEM) Note: Compared with the control group, ***p<0.001, ****p<0.0001, and *p<0.05 are considered statistically significant.

[0122] Table 4. Changes in mouse body weight in each group (Mean±SEM)

[0123] The experimental results show that gingerone A nanoparticles have a strong inhibitory effect on the proliferation of melanoma A375, which may be related to its unique ability to recognize cancer cells. After 21 days of administration, the tumor growth inhibition rate (TGI%) of gingerone A nanoparticles was 45.34%, which was superior to the 43.95% of the positive control drug dabrafenib. After 25 days of administration, gingerone A nanoparticles were superior to dabrafenib in terms of mean tumor volume, mean tumor weight, and body weight change rate in mice, demonstrating a significant inhibitory effect on melanoma A375. The GA@AMSN nanoparticle formulation has great application potential in the field of anti-melanoma treatment.

[0124] Furthermore, liver sections were collected from the GA@AMSN, 100 mg / kg treatment group for paraffin sectioning, and the morphology of cells and tissues was evaluated by H&E staining. The H&E staining results are shown in Figure 9. No significant abnormalities were found in the liver tissue structure; no fibrosis or mononuclear inflammatory cell infiltration was observed in the portal areas; and no obvious focal or patchy necrosis was observed in the liver parenchyma. No obvious sinusoidal congestion or cholestasis was observed, and no clear histological signs of liver tissue injury were found.

[0125] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. The application of a novel nano-formulation containing gingerone A in the preparation of antitumor drugs, characterized in that, The nanoformulation comprises aminated dendritic mesoporous silica and gingerone A supported on the aminated dendritic mesoporous silica.

2. The application according to claim 1, characterized in that, The tumors include one or more of the following: melanoma, lymphohematopoietic system tumors, endocrine tumors, lung and mediastinal tumors, breast tumors, digestive system tumors, urinary and male reproductive system tumors, female reproductive system tumors, head and neck tumors, central nervous system tumors, skin tumors, and bone and soft tissue tumors.

3. The application according to claim 1, characterized in that, The dosage forms of the drug include tablets, capsules, pills, injections, sustained-release preparations, or controlled-release preparations; The routes of administration of the antitumor drugs include one or more of the following: intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, rectal administration, skin and mucous membrane administration, and inhalation administration.

4. The application according to claim 1, characterized in that, The dosage of the nano-formulation in the antitumor drug is 100 mg / kg to 400 mg / kg.

5. The application according to claim 1, characterized in that, The anti-tumor drug is a drug that inhibits tumor growth or tumor cell proliferation.

6. The application according to claim 1, characterized in that, The antitumor drug is a drug that promotes or induces apoptosis in tumor cells.

7. The application according to claim 1, characterized in that, The anti-tumor drug is a drug that inhibits the growth of transplanted tumors.

8. The application according to any one of claims 1-7, characterized in that, The antitumor drug also contains pharmaceutically acceptable carriers, excipients, and / or excipients.

9. The application according to claim 1, characterized in that, The preparation method of the nano-formulation includes: Shogaol A is dissolved in a solvent to obtain a shogaol A solution. The shogaol A solution and aminated dendritic mesoporous silica are added to a buffer solution to react and load the shogaol A onto the aminated dendritic mesoporous silica to obtain the nano-formulation.

10. An antitumor drug, characterized in that, The active ingredient is a novel nano-formulation containing gingerone A; the nano-formulation is the nano-formulation used in any one of claims 1-9.

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